Systemic lupus erythematosus (SLE) is a chronic and potentially severe autoimmune disease which disproportionately affects women and African Americans (AA). Despite the role of environmental factors in modulating autoimmunity pathogenesis, the specific mechanisms by which it acts remain poorly understood. A growing body of evidence implicates the gut microbiota in the development of autoimmune disorders. In this study we will characterize the microbial composition (microbiome) and gene content (metagenome) of fecal DNA from samples obtained from AA patients with SLE, their unaffected first-degree relatives who show signs of autoimmunity, and healthy, unrelated, autoantibody-negative AA controls. The overall hypothesis of this proposal is that there is gut microbial variation at both the structural and functional level between individuals that influences development of autoimmunity and autoimmune disease. We will test this hypothesis by accomplishing 3 Specific Aims: 1) Testing the hypothesis that gut community structure (microbiome) correlates with markers of autoimmunity and SLE disease. 2) Testing the hypothesis that the microbiome's genes, variants and functional capabilities (metagenome) are associated with autoimmunity and SLE disease. 3) Testing the hypothesis that the gut microbial composition correlates with markers of autoimmunity and SLE disease in a multivariate model, taking into account host genotype data, phenotypic traits, diet and other exposures. Upon completion of these Aims we will have systematically identified bacterial biomarkers (e.g. SNPs, genes, strains) that correlate with SLE, can be investigated in other autoimmune diseases, and serve as potential targets for disease treatment.